Background Art
This invention relates to receptors for adhesion peptides, and more specifically to a novel receptor subunit having affinity for extracellular matrix molecules.
Multicellular organisms, such as man, have some 1014 cells which can be divided into a minimum of fifty different types, such as blood cells and nerve cells. During the course of growth and development, cells adhere to other cells, or to extracellular materials, in specific and orderly ways. Such cell adhesion mechanisms appear to be of importance in mediating patterns of cellular growth, migration and differentiation, whereby cells develop specialized characteristics so as to function as, for example, muscle cells or liver cells. Cell adhesion mechanisms are also implicated in dedifferentiation and invasion, notably where cells lose their specialized forms and become metastasizing cancer cells.
The mechanisms underlying the interactions of cells with one another and with extracellular matrices are not fully understood, but it is thought that they are mediated by cell surface receptors which specifically recognize and bind to a cognate ligand on the surface of cells or in the extracellular matrix.
The adhesion of cells to extracellular matrices and their migration on the matrices is mediated in many cases by the binding of a cell surface receptor to an Arg-Gly-Asp containing sequence in the matrix protein, as reviewed in Ruoslahti and Pierschbacher, Science 238:491-497 (1987). The Arg-Gly-Asp sequence is a cell attachment site at least in fibronectin, vitronectin, fibrinogen von Willibrand, thrombopondin, osteopontin, and possibly various collagens, laminin and tenascin. Despite the similarity of their cell attachment sites, these proteins can be recognized individually by their interactions with specific receptors.
The integrins are a large family of cell surface glycoproteins that mediate cell-to-cell and cell-to-matrix adhesion as described, for example, in the Ruoslahti and Pierschbacher article cited above. All known members of this family of adhesion receptors are heterodimers consisting of an xcex1 and a xcex2 subunit noncovalently bound to each other. When the integrin family was first identified, integrins were grouped into three subfamilies based on the three xcex2 subunits that were initially recognized (xcex21, xcex22 and xcex23). Over the past few years, the primary structures of three integrin xcex2 subunits from mammalian cells and one from Drosophila have been deduced from cDNA.
Each xcex1 subunit was thought to associate uniquely with a single xcex2 subunit. Eleven distinct xcex1 subunits have thus far been described. As new integrins have been identified, however, it has become clear that this grouping is not entirely satisfactory, since there are clearly more than three xcex2 subunits and since some xcex1 subunits can associate with more than one xcex2 subunit as described, for example, in Sonnenberg et al., J. Biol. Chem. 265:14030-14038 (1988).
Because of the importance of integrins in mediating critical aspects of both normal and abnormal cell processes, a need exists to identify and characterize different integrins. The present invention satisfies this need and provides related advantages as well.
The present invention relates to a substantially purified xcex2 subunit of an integrin cell surface receptor designated as xcex26. The amino acid sequence of human xcex26 (SEQ ID NO:27) is provided in FIG. 3.
The present invention also relates to amino acid fragments specific to xcex26 that have a variety of uses. The invention further relates to vectors having a gene encoding such fragments. Host cells containing such vectors are also provided. The nucleic acids encoding xcex26 as well as nucleic acids that specifically hybridize with the nucleic acids encoding xcex26 sequences are other aspects of the present invention.
In a further aspect, the present invention relates to a substantially purified integrin comprising xcex26 bound to an xcex1 subunit, particularly xcex1V or xcex1F. Methods of blocking the attachment of the xcex26-containing integrins to its ligand and of detecting the binding of such integrins to its ligand are also provided.
The present invention also relates to methods of increasing or decreasing cell adhesion in cells expressing a xcex26-containing integrin by overexpressing the integrin or by binding the integrin with a ligand, such as vitronectin.